This Program Project represents an integrated exploration of key aspects of the neurobiology of the basal ganglia, both in intact animals and in animals sustaining lesions of the dopamine (DA)- containing nigrostriatal projections. In many animals, the neurotoxin 6-hydroxydopamine will be administered intracerebrally to adult rats to produce an animal models of Parkinsonism. We have identified seven interrelated themes, each of which appear in most if not all of the projects; (1) nonsynaptic interactions between neuronal elements in striatum; (2) direct versus indirect output pathways of dorsal striatum (3) the relation between D1 and D2 receptors on medium spiny neurons of straitum; (4) DA-interactions with other neurochemically defined neuronal elements; (5) pathology and pathogenesis related to Parkinsonism; (6) compensations that occur in response to partial lesions of monoaminergic pathways; and (7) the impact of L-DOPA on neural functioning and on behavior. As part of this endeavor, a multi-disciplinary characterization of many aspects of the normal basal ganglia will be required. Include in this characterization will be an anatomical and neurochemical examination of the interactions among dopaminergic, cholinergic, glutamatergic, and GABAergic neurons. An in-depth study of the catecholamine-synthesizing enzyme, tyrosine hydroxylase also will be carried out. Among the clinically-related issues to be examined are (1) the neurobiological basis of the pre-clinical and the clinical phase of Parkinsonism and related disorders, (2) mechanisms of action of L-DOPA in Parkinsonism, and (3) the underlying basis of the selective vulnerability of nigrostriatal DA neurons. It is expected that these studies will provide insights into the relation between neuropathology and symptomatology in a variety of neurodegerative disorders will be of value in developing new modes of therapy for these conditions, and will add important new information concerning the neurobiology of the basal ganglia.